This invention relates to compositions of matter classified in the art of chemistry as amine derivatives of 5,8-methano-benzocyclohexane, 5,8-methano-benzocycloheptane, 5,9-methano-benzocycloheptane, 5,9-methano-benzocyclooctane, 5,10-methano-benzocyclooctane, 5,10-methanobenzocyclononane, 5,11-methano-benzocyclononane, 5,11-methanobenzocyclodecane, 5,12-methanobenzocyclodecane, or 5,12-methanobenzocycloundecane, and the non-toxic acid addition salts thereof, which in standard pharmacological tests in animals exhibit analgesic and anti-inflammatory activity, and to processes for making and using such compositions.
5,6,7,8,9,10-Hexahydro-5,9-methano-benzocycloocten-11-amine, 5,6,7,8,9,10-hexahydro-5,9-methano-benzocycloocten-11-one, oxime, and 5,6,7,8,9,10-hexahydro-5,9-methano-benzocyclooctene-11-one have been prepared by Mitsuhashi et al., Chem. Pharm. Bull. (Tokyo), 18, p. 75 (1970). The primary amine was also converted to the corresponding N,N-dimethyl tertiary amine. Although this publication sets forth that the compounds were synthesized as part of a study of structure activity relationships of analgetics, no biological data is given for any compound prepared, and the only reported studies for the compounds are of their spectral properties. No other reports of any practical utility for any of the reference compounds are known.
The structure of the tricyclic reference compounds differs from the tricyclic compounds derived from tetralone of this application in one major particular. This difference is the nature of the carbon atom at the benzylic bridgehead position of the ring system. In the reference compounds this is never other than a tertiary carbon atoms while in the compounds of this application this is always a quaternary carbon atoms. This variation leads to two important distinctions, in addition to the aforesaid lack of any teaching by the reference of practical utility, between the reference compounds and those of this application.
It is currently accepted that the ability of a particular compound to induce analgesia depends inter alia on its ability to fit a particular "receptor site". The steric and spatial relationships in the immediate vicinity of the amino group of known analgesics and their close analogs which do not possess this activity to any significant degree indicates that the area in the immediate vicinity of the amino group is critical for fit with the hypothesized "receptor site". The change to a quaternary carbon atom at a position .alpha. to the amino substituent introduces a completely different steric environment near the amino group from that of the compounds of Mitsuhashi.
The change to quaternary carbon also makes the method of synthesis taught by Mitsuhashi inapplicable to any of the compounds of this application. Mitsuhashi's synthesis besides being limited only to benzocyclooctene compounds is limited by the eneamine alkylation used to initiate the sequence. It has been a known advantage of eneamine alkylations of ketonic compounds since their discovery that in contrast to other alkylation methods only one substituent can be introduced in the position .alpha. to the carbonyl group. If a substituent is already present at that position a second cannot be introduced.
A discussion representing the generally accepted reasons for the unique behavior of this reaction is set forth by Williamson in Tetrahedron, 3, 314 (1958).
The structure of pyrrolidine eneamines may be depicted as formula XX or XXa: ##SPC1##
Form XXa is that involved in the reaction.
Examination of Barton Models (D. H. R. Barton, Chem. and Ind., 1136 (1956)) of .alpha.-methylated cyclohexanone (XXI) and 5-phthalimido-2-tetralone (XXII, R=phthalimido) eneamines shows that a combination of steric factors due to the pyrrolidine ring and .alpha.-alkyl substitution prevents the introduction of a second alkyl group. These models, when measured, give values of about 1 and 1.4 Angstroms respectively for the distances of the .alpha. hydrogen atom of the pyrrolidine ring and the nearest hydrogen atoms of the methyl group when these are equatorial. These are comparable to the "interference radii" of two hydrogen atoms (1.5 Angstroms) Crombie Cromobie (See for example E. A. Braude and F. Sondheimer, J. Chem. Soc., 3754(1955)). The methyl groups must therefore take up the axial position in the active forms XXI and XXII so that equatorial substitution is blocked by the pyrrolidine ring and in the case of XXI axial substitution in the 6-position is also blocked by the axial methyl group. If the .alpha.-methyl groups in XXI and XXII were to remain equatorial then coplanarity of the four bonds from the C=N.sup.+ group [a necessary condition for the existence of forms XXI and XXII (Dewar, Electronic Theory of Organic Chemistry, Chapter I, Oxford University Press (1948))] would be prevented, C-alkylation would again be inhibited. Of course, in those cases which whic C-alkylation proceeds by rearrangement of N-alkylated forms, arguments involving the stereo chemistry of form (XXa) do not apply. The Mitsuhashi synthesis is not considered to involve an N-alkylated form in the initial substitution. ##SPC2##